ADA 2023: The only nonstatin therapy to reduce risk for 4-point MACE in ASCVD may potentially find a role in primary prevention as well, though caution is advised.
The findings, reported at the 83rd Scientific Sessions of the American Diabetes Association (ADA), come from a prespecified subgroup analysis of the primary prevention cohort in the CLEAR Outcomes trial.1 The analysis also found that bempedoic acid in this population reduced the risk for CV death by 39%, for all-cause death by 27%, and for myocardial infarction (MI) by 39%,1 outcomes that the study’s lead author Steven Nissen, MD, calls “a wake-up call for the clinical community that patients with risk factors for coronary disease and high cholesterol, particularly those with diabetes, should be treated with a cholesterol-lowering drug.”2
“We know early prevention measures are critical to slowing the progression of heart disease, especially for people with comorbidities like diabetes,” said Nissen, chief academic officer of the Heart, Vascular, and Thoracic Institute at Cleveland Clinic in an ADA news release. “Unfortunately, less than half of patients in the US similar to the study patient population are being treated with cholesterol-lowering drugs – leaving them at risk.”2
CLEAR Outcomes, a 13 970-participant study unique for its inclusion of only individuals declaring statin intolerance , was the first to demonstrate the benefits of a non-statin lipid lowering therapy on a 4-point composite of major adverse cardiovascular events (MACE).3 Pooled data from the original study, which included participants from both primary and secondary prevention populations, demonstrated that the ATP citrate lyase inhibitor reduced the composite MACE endpoint by 13% compared to placebo, including a 23% lower risk for fatal or nonfatal myocardial infarction (MI).3
For their current exploration, Nissen and colleagues analyzed CLEAR Outcomes data from the 4206 original participants at high risk for CVD but without a prior event. Among this subgroup, 2100 had been randomly assigned to receive bempedoic acid 180 mg daily and 2106 to receive placebo. Mean age in this cohort was 68 years, 59% were women, approximately 90% were White, and 66% had a diagnosis of diabetes.1
The primary outcome of interest for CLEAR Outcomes was first occurrence of any component of the 4-point MACE composite of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization.
Investigators followed the subgroup for a median of 39.9 months and reported at the ADA sessions a 30% reduction in relative risk for the primary endpoint of 4-point MACE (adjusted HR, 0.70; 95% CI, 0.55-0.89; P=.002) among participants receiving bempedoic acid vs those receiving placebo. Nissen et al reported also that use of bempedoic acid was associated with a 36% reduction in risk for a 3-point composite of CV death, MI, or stroke (aHR, 0.64; 95% CI, 0.48-0.84; P<.001).
When they analyzed the individual components of that composite the researchers observed a 39% reduction in risk for MI vs placebo (aHR, 0.61; 95% CI, 0.39-0.98), a 39% reduction in risk for CV death (aHR, 0.61; 95% CI, 0.41-0.92), and a 27% reduction in risk for all-cause mortality (aHR = 0.73; 95% CI, 0.54-0.98). Nissen and colleagues reported no significant effect of bempedoic acid treatment on risk of stroke or coronary revascularization.
After a thorough review of both strengths and limitations of the subanalysis, Dhruv Kazi, MD, associate director of the Smith Center for Outcomes Research and director of the Cardiac Critical Care Unit at Beth Israel Deaconess Medical Center, in Boston, MA, wrote in an accompanying editorial in JAMA that bempedoic acid for high-risk primary CVD prevention is “not a statin substitute, but a good plan B.” He emphasized that these apparently remarkable findings notwithstanding, clinicians should continue to consider statins as first-line therapy for primary prevention in patients who can tolerate them.4
His reasons are many and include the comparatively larger LDL-C reductions seen with statins vs bempedoic acid (50% vs 16% over 4 years); the long-term safety and efficacy of statins supported by years of evidence; the frequent success of a statin rechallenge after initial intolerance; and the branded status of bempedoic acid (Nexletol, Esperion) that makes it far more costly than a generic statin.4
For clinicians wondering whether bempedoic acid has a place in clinical practice, Kazi says that the medication is “an effective therapeutic option for appropriately selected statin-intolerant individuals” whose risk is similar to the CLEAR Outcomes primary prevention cohort (ie, elevated predicted CV risk, elevated CAC scores, or comorbid T2D). Even then, he cautions, “bempedoic acid should not be considered a substitute for statins, which remain the first-line therapy for primary prevention.”4